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ARTICLE

Benefits and Harms of Doxycycline Treatment for Gulf War Veterans' Illnesses

A Randomized, Double-Blind, Placebo-Controlled Trial

right arrow Sam T. Donta, MD; Charles C. Engel, Jr., MD, MPH; Joseph F. Collins, ScD; Joel B. Baseman, PhD; Lisa L. Dever, MD; Thomas Taylor, MD; Kathy D. Boardman, RPh; Lewis E. Kazis, ScD; Suzanne E. Martin; Rebecca A. Horney, BS; Annette L. Wiseman; Douglas S. Kernodle, MD; Raymond P. Smith, MD; Aldona L. Baltch, MD; Christine Handanos, MD; Brian Catto, MD; Luis Montalvo, MD; Michael Everson, PhD; Warren Blackburn, MD; Manisha Thakore, MD; Sheldon T. Brown, MD; Larry Lutwick, MD; Dorothy Norwood, MD; Jack Bernstein, MD; Catherine Bacheller, MD; Bruce Ribner, MD; L. W. Preston Church, MD; Kenneth H. Wilson, MD; Prabhakar Guduru, MD; Robert Cooper, MD; Joseph Lentino, MD; Richard J. Hamill, MD; Arnold B. Gorin, MD; Victor Gordan, MD; David Wagner, MD; Cliff Robinson, MD; Pierre DeJace, MD; Ronald Greenfield, MD; Lisa Beck, MD; Marvin Bittner, MD; H. Ralph Schumacher, MD; Fredric Silverblatt, MD; James Schmitt, MD; Edward Wong, MD; Margaret A.K. Ryan, MD, MPH; Javier Figueroa, MD; Christopher Nice, MD; John R. Feussner, MD, MPH, the VA Cooperative #475 Group

20 July 2004 | Volume 141 Issue 2 | Pages 85-94

Background: It has been hypothesized that certain Mycoplasma species may cause Gulf War veterans' illnesses (GWVIs), chronic diseases characterized by pain, fatigue, and cognitive symptoms, and that affected patients may benefit from doxycycline treatment.

Objective: To determine whether a 12-month course of doxycycline improves functional status in Gulf War veterans with GWVIs.

Design: A randomized, double-blind, placebo-controlled clinical trial with 12 months of treatment and 6 additional months of follow-up.

Setting: 26 U.S. Department of Veterans Affairs and 2 U.S. Department of Defense medical centers.

Participants: 491 deployed Gulf War veterans with GWVIs and detectable Mycoplasma DNA in the blood.

Intervention: Doxycycline, 200 mg, or matching placebo daily for 12 months.

Measurements: The primary outcome was the proportion of participants who improved more than 7 units on the Physical Component Summary score of the Veterans Short Form-36 General Health Survey 12 months after randomization. Secondary outcomes were measures of pain, fatigue, and cognitive function and change in positivity for Mycoplasma species at 6, 12, and 18 months after randomization.

Results: No statistically significant differences were found between the doxycycline and placebo groups for the primary outcome measure (43 of 238 participants [18.1%] vs. 42 of 243 participants [17.3%]; difference, 0.8 percentage point [95% CI, –6.5 to 8.0 percentage points]; P > 0.2) or for secondary outcome measures at 1 year. In addition, possible differences in outcomes at 3 and 6 months were not apparent at 9 or 18 months. Participants in the doxycycline group had a higher incidence of nausea and photosensitivity.

Limitations: Adherence to treatment after 6 months was poor.

Conclusion: Long-term treatment with doxycycline did not improve outcomes of GWVIs at 1 year.


Editors' Notes
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Context

  • Some experts hypothesize that Mycoplasma species cause Gulf War veterans' illnesses (GWVIs).

Contribution

  • In this double-blind trial, 491 deployed Gulf War veterans with GWVIs and detectable Mycoplasma DNA in their blood were randomly assigned to receive either doxycycline, 200 mg, or matching placebo daily for 1 year. There were no long-term differences between the 2 groups in physical or mental function or in pain or fatigue symptoms. Patients given doxycycline had nausea and photo-sensitivity more often than did patients given placebo.

Implications

  • Long-term doxycycline treatment probably doesn't benefit veterans with GWVIs and may harm them.

–The Editors

 

Author and Article Information
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From Veterans Affairs Medical Centers (Boston, Massachusetts; Milwaukee, Wisconsin; Montgomery, Alabama; Perry Point, Maryland; East Orange, New Jersey; White River Junction, Vermont; Albuquerque, New Mexico; Bedford, Massachusetts; Nashville, Tennessee; Albany, New York; Augusta, Georgia; Birmingham, Alabama; Bronx, New York; Brooklyn, New York; Dayton, Ohio; Charleston, South Carolina; Durham, North Carolina; Fargo, North Dakota; Hines, Illinois; Houston, Texas; Manchester, New Hampshire; New Orleans, Louisiana; Oklahoma City, Oklahoma; Omaha, Nebraska; Philadelphia, Pennsylvania; Providence, Rhode Island; Richmond, Virginia; and San Juan, Puerto Rico); Uniformed Services University of the Health Sciences, Bethesda, Maryland; University of Texas Health Science Center, San Antonio, Texas; Naval Health Research Center, San Diego, California; and Department of Veterans Affairs National Central Office, Washington, DC.

Disclaimer: The views expressed by authors associated with military institutions are their own and not the official position of any university, medical center, or department of the U.S. government.

Note: SF-36 is a registered trademark of the Medical Outcomes Trust.

Grant Support: By the Cooperative Studies Program of the U.S. Department of Veterans Affairs Office of Research and Development and the U.S. Department of Defense. Pfizer Inc. donated the study drug and placebo.

Potential Financial Conflicts of Interest:Employment: R.P. Smith (U.S. Department of Veterans Affairs), A.L. Baltch (U.S. Department of Veterans Affairs), S.T. Brown (U.S. Department of Veterans Affairs); Consultancies: C.C. Engel Jr. (U.S. Department of Defense), M. Bittner (Pfizer); Honoraria: J. Lentino (Pfizer), R. Greenfield (Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, Abbott, Merck, Wyeth), M. Bittner (Pfizer); Grants received: R.P. Smith (U.S. Department of Veterans Affairs), M. Bittner (Pfizer).

Requests for Single Reprints: Joseph F. Collins, ScD, Veterans Affairs Maryland Healthcare System, Cooperative Studies Program Coordinating Center (151 E), PO Box 1010, Perry Point, MD 21902.

Current Author Addresses: Dr. Donta: Boston Veterans Affairs Medical Center, 151 South Huntington Avenue, Boston, MA 02130.

Dr. Engel: Department of Psychiatry, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20815.

Dr. Collins, Ms. Horney, and Ms. Wiseman: Veterans Affairs Maryland Health Care System, Cooperative Studies Program Coordinating Center (151E), PO Box 1010, Perry Point, MD 21902.

Dr. Baseman: Department of Microbiology, University of Texas Health Sciences Center, 7703 Floyd Curl Drive, San Antonio, TX 78284.

Dr. Dever: Veterans Affairs New Jersey Health Care System, 385 Tremont Avenue, East Orange, NJ 07018.

Dr. Taylor: White River Junction Veterans Affairs Hospital, 215 North Main Street, White River Junction, VT 05008.

Ms. Boardman: Cooperative Studies Program, 2401 Centre Avenue SE, Albuquerque, NM 87106.

Dr. Kazis: Boston University School of Public Health, 715 Albany Street, T3-W, Boston, MA 02118.

Ms. Martin: Cell Signaling Technology, Inc., 166 B Cummings Center, Beverly, MA 01915.

Dr. Kernodle: Nashville Veterans Affairs Medical Center, 1310 24th Avenue South, Nashville, TN 37212-2637.

Drs. Smith and Baltch: Stratton Veterans Affairs Medical Center, 113 Holland Avenue, Albany, NY 12208.

Dr. Handanos: Veterans Affairs Medical Center, 1501 San Pedro SE, Albuquerque, NM 87108.

Drs. Catto and Montalvo: Veterans Affairs Medical Center Augusta, 1 Freedom Way (235), Augusta, GA 30904.

Dr. Everson: Capstone Clinical, 1222 14th Avenue South, Suite 208, Birmingham, AL 35205.

Dr. Blackburn: Birmingham Veterans Affairs Medical Center, 700 19th Street, Birmingham, AL 35233.

Dr. Thakore: VA Medical Center (151), 150 Huntington Avenue, Boston, MA 02130.

Dr. Brown: Bronx Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468.

Drs. Lutwick and Norwood: Veterans Affairs New York Harbor Health Care System, 800 Poly Place, Brooklyn, NY 11209.

Dr. Bernstein: Veterans Affairs Medical Center, 4100 West Third Avenue, Dayton, OH 45429.

Dr. Bacheller: Wright State University/Veterans Affairs, 4000 West Third Street, Dayton, OH 45429.

Dr. Ribner: Emory University, 1364 Clifton Road NE, Atlanta, GA 30322.

Dr. Church: Veterans Affairs Medical Center, 109 Bee Street, Charleston, SC 29403.

Dr. Wilson: Veterans Affairs Medical Center, 508 Fulton Street, Durham, NC 27705.

Drs. Guduru and Cooper: Veterans Affairs Medical Center, 2101 North Elm Street, Fargo, ND 58102.

Dr. Lentino: Hines Veterans Affairs Hospital, Fifth Avenue at Roosevelt Road, Hines, IL 60141.

Dr. Hamill: Veterans Affairs Medical Center (111G), 2002 Holcombe Boulevard, Houston, TX 77030.

Dr. Gorin: Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030.

Dr. Gordan: Veterans Affairs Medical Center, 718 Smyth Road, Manchester, NH 03104.

Dr. Wagner: Zablocki Veterans Affairs Medical Center, 5000 West National Avenue, Milwaukee, WI 53295.

Dr. Robertson: Central Alabama Veterans Health Care System, 215 Perry Hill Road, Montgomery, AL 36109.

Dr. DeJace: Veterans Affairs Medical Center, 1601 Perdido Street, New Orleans, LA 70112.

Drs. Greenfield and Beck: Oklahoma City Veterans Affairs Medical Center, 921 NE 13th Street, Oklahoma City, OK 73104.

Dr. Bittner: Veterans Affairs Medical Center, 4101 Woolworth Avenue (111D), Omaha, NE 68105.

Dr. Schumacher: Veterans Affairs Medical Center (151K), University and Woodland Avenues, Philadelphia, PA 19104.

Dr. Silverblatt: Providence Veterans Affairs Medical Center, 830 Chalkstone Avenue, Providence, RI 02908.

Drs. Schmitt and Wong: McGuire Veterans Affairs Medical Center, 1201 Broad Rock Boulevard, Richmond, VA 23249.

Dr. Ryan: Branch Medical Clinic, Naval Training Center, 2659 Stockton Road, Room A203, San Diego, CA 92106.

Dr. Figueroa: Veterans Affairs Medical Center, 10 Casia Street, San Juan, Puerto Rico 00921.

Dr. Nice: Veterans Affairs Hospital, North Main Street, White River Junction, VT 05001.

Dr. Feussner: Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425.

Author Contributions: Conception and design: S.T. Donta, C.C. Engel Jr., J.F. Collins, J.B. Baseman, L.E. Kazis, R.A. Horney, A.L. Wiseman, V. Gordan, P. DeJace, M. Bittner, H.R. Schumacher, J.R. Feussner.

Analysis and interpretation of the data: S.T. Donta, C.C. Engel Jr., J.F. Collins, J.B. Baseman, L.L. Dever, T. Taylor, L.E. Kazis, S.E. Martin, R.A. Horney, A.L. Wiseman, K.H. Wilson, D. Wagner, P. DeJace, M. Bittner, F. Silverblatt, M.A.K. Ryan, J.R. Feussner.

Drafting of the article: S.T. Donta, C.C. Engel Jr., J.F. Collins, J.B. Baseman, T. Taylor, S.E. Martin, R.P. Smith, A.B. Gorin, P. DeJace, M. Bittner, J.R. Feussner.

Critical revision of the article for important intellectual content: S.T. Donta, C.C. Engel Jr., J.F. Collins, J.B. Baseman, L.L. Dever, T. Taylor, K.D. Boardman, L.E. Kazis, S.E. Martin, D.S. Kernodle, S.T. Brown, D. Wagner, M. Bittner, H.R. Schumacher, F. Silverblatt, M.A.K. Ryan, J.R. Feussner.

Final approval of the article: S.T. Donta, C.C. Engel Jr., J.F. Collins, L.L. Dever, T. Taylor, K.D. Boardman, R.P. Smith, A.L. Baltch, C. Handanos, L. Montalvo, W. Blackburn, S.T. Brown, L. Lutwick, J. Bernstein, C. Bacheller, K.H. Wilson, R. Cooper, R.J. Hamill, V. Gordan, D. Wagner, P. DeJace, R. Greenfield, M. Bittner, H.R. Schumacher, F. Silverblatt, J. Schmitt, E. Wong, M.A.K. Ryan, C. Nice, J.R. Feussner.

Provision of study materials or patients: S.T. Donta, C.C. Engel Jr., L.L. Dever, T. Taylor, K.D. Boardman, D.S. Kernodle, R.P. Smith, A.L. Baltch, C. Handanos, B. Catto, L. Montalvo, M. Everson, W. Blackburn, M. Thakore, B. Ribner, L.W.P. Church, K.H. Wilson, P. Guduru, R.J. Hamill, A.B. Gorin, V. Gordan, D. Wagner, C. Robinson, P. DeJace, R. Greenfield, L. Beck, M. Bittner, H.R. Schumacher, F. Silverblatt, J. Schmitt, E. Wong, M.A.K. Ryan, J. Figueroa, C. Nice.

Statistical expertise: J.F. Collins.

Obtaining of funding: J.F. Collins, A.L. Wiseman.

Administrative, technical, or logistic support: J.F. Collins, S.E. Martin, R.A. Horney, A.L. Wiseman, D. Norwood, A.B. Gorin, D. Wagner, L. Beck, C. Nice, J.R. Feussner.

Collection and assembly of data: J.F. Collins, J.B. Baseman, T. Taylor, R.A. Horney, A.L. Wiseman, D.S. Kernodle, A.L. Baltch, C. Handanos, B. Catto, L. Montalvo, M. Everson, W. Blackburn, M. Thakore, S.T. Brown, L. Lutwick, D. Norwood, J. Bernstein, C. Bacheller, B. Ribner, P. Guduru, R. Cooper, J. Lentino, A.B. Gorin, D. Wagner, R. Greenfield, L. Beck, H.R. Schumacher, J. Schmitt, E. Wong, M.A.K. Ryan, C. Nice.

 

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